IL-18 mediates proapoptotic signaling in renal tubular cells through a Fas ligand-dependent mechanism

Hongji Zhang, Karen L. Hile, Hiroshi Asanuma, Brian Vanderbrink, Ethan I. Franke, Matthew T. Campbell, Kirstan K. Meldrum

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Renal tubular cell apoptosis is a significant component of obstruction-induced renal injury, and it results in a progressive loss in renal parenchymal mass during renal obstruction. Although IL-18 is an important mediator of inflammatory renal disease and renal fibrosis, its role in obstruction-induced renal tubular cell apoptosis remains unclear. To study this, male C57BL6 wild-type mice and C57BL6 mice transgenic for human IL-18-binding protein (IL-18BP Tg) were subjected to renal obstruction vs. sham operation. The kidneys were harvested after 1 or 2 wk and analyzed for IL-18 production, apoptosis, caspase activity, and Fas/Fas Ligand (FasL) expression. HK-2 cells were similarly analyzed for apoptosis and proapoptotic signaling following 3 days of direct exposure to IL-18 vs. control media. Renal obstruction induced a significant increase in IL-18 production, renal tubular cell apoptosis, caspase activation, and FasL expression. IL-18 neutralization, on the other hand, significantly reduced obstruction-induced apoptosis, caspase-8 and caspase-3 activity, and FasL expression. In vitro experiments similarly demonstrate that IL-18 stimulation induces apoptosis, FasL expression, and increases active caspase-8 and caspase-3 expression in a dose-dependent fashion. siRNA knockdown of FasL gene expression, however, significantly reduced IL-18-induced apoptosis. This study reveals that IL-18 is a significant mediator of obstruction-induced tubular cell apoptosis, and it demonstrates that IL-18 stimulates proapoptotic signaling through a FasL-dependent mechanism.

Original languageEnglish
Pages (from-to)F171-F178
JournalAmerican Journal of Physiology - Renal Physiology
Volume301
Issue number1
DOIs
Publication statusPublished - 2011 Jul 1
Externally publishedYes

Keywords

  • Apoptosis
  • Cytokine
  • Kidney
  • Renal dysfunction

ASJC Scopus subject areas

  • Physiology
  • Urology

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